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Introduction: Mutations occurring in the spike (S) protein of SARS-CoV-2 enables the virus to evade COVID-19 vaccine- and infection-induced immunity. Methods: Here we provide a comprehensive analysis of humoral and cell-mediated immunity in 111 healthcare workers who received three or four vaccine doses and were followed up to 12 and 6 months, respectively, after the last vaccine dose. Omicron breakthrough infection occurred in 71% of the vaccinees, enabling evaluation of vaccine- and vaccine/infection-induced hybrid immunity. Results: Neutralizing antibodies were the highest against the ancestral D614G and were sequentially reduced against the Omicron variants BA.2, BA.5 and XBB.1.5. S1-specific IgG and neutralizing antibody levels were significantly higher in infected than in uninfected vaccinees, and the fourth vaccine dose in combination with a breakthrough infection resulted in high neutralizing antibody levels against all variants. T cell-mediated immunity, instead, was well retained already after two vaccine doses, and was not significantly strengthened by additional booster vaccine doses or Omicron breakthrough infections. Discussion: While humoral immunity is sensitive to mutations in the S protein and thus declined rapidly, the cell-mediated immunity is durable to antigenic variation, which may explain the good efficacy of COVID-19 vaccines against a severe disease. [ABSTRACT FROM AUTHOR]

After 4 years of the COVID-19 pandemic, SARS-CoV-2 continues to circulate with epidemic waves caused by evolving new variants. Although the rapid development of vaccines and approved antiviral drugs has reduced virus transmission and mitigated the symptoms of infection, the continuous emergence of new variants and the lack of simple-use (non-hospitalized, easy timing, local delivery, direct acting, and host-targeting) treatment modalities have limited the effectiveness of COVID-19 vaccines and drugs. Therefore, novel therapeutic approaches against SARS-CoV-2 infection are still urgently needed. As a positive-sense single-stranded RNA virus, SARS-CoV-2 is highly susceptible to RNA interference (RNAi). Accordingly, small interfering (si)RNAs targeting different regions of SARS-CoV-2 genome can effectively block the expression and replication of the virus. However, the rapid emergence of new SARS-CoV-2 variants with different genomic mutations has led to the problem of viral escape from the targets of RNAi strategy, which has increased the potential of off-target effects by siRNA and decreased the efficacy of long-term use of siRNA treatment. In our study, we enzymatically generated a set of Dicer-substrate (D)siRNA swarms containing DsiRNAs targeting single or multiple conserved sequences of SARS-CoV-2 genome by using in vitro transcription, replication and Dicer digestion system. Pre-transfection of these DsiRNA swarms into Vero E6-TMPRSS2 cells inhibited the replication of several SARS-CoV-2 variants, including the recent Omicron subvariants BQ.1.1 and XBB.1.5. This in vitro investigation of novel DsiRNA swarms provides solid evidence for the feasibility of this new RNAi strategy in the prevention and treatment of SARS-CoV-2 infection. [ABSTRACT FROM AUTHOR]

Highly pathogenic avian influenza (HPAI) H5N1 is known for its virulence and zoonotic potential, infecting birds and mammals, thus raising public health concerns. Since 2021 its spread among birds has led to cross-species transmission causing epizootics among mammals, eventually impacting fur animal farms in Finland in 2023. To analyze the infectivity of the Finnish H5N1 isolates in human cells, representatives of diverse H5N1 isolates were selected based on the genetic differences, host animal species, and the year of occurrence. The infection kinetics of the selected H5N1 isolates from wild pheasant and fox, and fur animals blue fox and white mink were examined in human monocyte-derived dendritic cells (moDCs) with H5N1 human isolate as a control. Although the isolate from pheasant (a wild bird) showed weakly reduced replication and viral protein expression in human cells compared to mammalian isolates, no discernible differences in virus replication in moDCs was observed. This study revealed similar infectivity in human moDCs for all five H5N1 isolates, regardless of the observed genetic differences. While H5N1 human infections remain rare, the virus poses a risk for widespread epizootics in mammals such as fur animal farms and, more recently, dairy cattle.